Effects of 5-HT-releasing agents on the extracellullar hippocampal 5-HT ofrats. Implications for the development of novel antidepressants with a short onset of action

The effects of two selective 5-HT-releasing agents, 4-methylthioamphetamine (MTA) and 5-methoxy-6-methyl-2-aminoindan (MMAI), on the extracellular 5-H T concentration in the dorsal hippocampus was determined by microdialysis i n anesthetized rats. After i.p. administration of 1 or 5 mg/kg of either co mpound, a rapid and significant increase of 5-HT basal release was observed . MTA (5 mg/kg) induced a maximal increase of about 2000% over the basal va lue 40 min after injection, which declined slowly, whereas MMAI (5 mg/kg) i nduced a maximal response of about 1350% which showed a rapid decline. Mono amine oxidase-A inhibitory properties of MTA, and MMAI's lack of similar pr operties might account for the difference between the two compounds. In agr eement with previous information, a much lower increase in hippocampal 5-HT was observed in response to systemic fluoxetine. This difference in the ma gnitude of the response after MTA or MMAI and fluoxetine indicates that dif ferent mechanisms of action are operating. Based on evidence showing that a n acute enhancement of 5-HT neurotransmission might result in the rapid app earance of therapeutic effects of serotonergic antidepressants, we suggest that MTA and MMAI might serve as leads for a novel family of compounds with a short onset of action useful for treating depression. (C) 1999 Elsevier Science Ltd. All rights reserved.